Vulnerability to environmental and climatic health provocations among women and men hospitalized with chronic heart disease: insights from the RESILIENCE TRIAL cohort

Aims: We aimed to recruit a representative cohort of women and men with multi-morbid chronic heart disease as part of a trial testing an innovative, nurse-co-ordinated, multi-faceted intervention to lower rehospitalization and death by addressing areas of vulnerability to external challenges to their health. Methods and results: The prospective, randomized open, blinded end-point RESILIENCE Trial recruited 203 hospital inpatients (mean age 75.7 ± 10.2 years) of whom 51% were women and 94% had combined coronary artery disease, heart failure, and/or atrial fibrillation. Levels of concurrent multi-morbidity were high (mean Charlson Index of Comorbidity Score 6.5 ± 2.7), and 8.9% had at least mild frailty according to the Rockwood Clinical Frailty Scale. Including the index admission, 19–20% of women and men had a pre-existing pattern of seasonally linked hospitalization (seasonality). Detailed phenotyping revealed that 48% of women and 40% of men had ≥3 physiological factors, and 15% of women and 16% of men had ≥3 behavioural factors likely to increase their vulnerability to external provocations to their health. Overall, 61–62% of women and men had ≥4 combined factors indicative of such vulnerability. Additional factors such as reliance on the public health system (63 vs. 49%), lower education (30 vs. 14%), and living alone (48 vs. 29%) were more prevalent in women. Conclusion: We successfully recruited women and men with multi-morbid chronic heart disease and bio-behavioural indicators of vulnerability to external provocations to their health. Once completed, the RESILIENCE TRIAL will provide important insights on the impact of addressing such vulnerability (promoting resilience) on subsequent health outcomes

Novel approaches to risk stratification in common cardiovascular diseases using circulating and imaging biomarkers

© 2021 Jay Kumar Manohar RamchandCardiovascular disease (CVD) is a leading cause of morbidity and mortality. The number of individuals at risk of CVD complications continues to rise, making CVD preventative strategies an ongoing public health priority. Current risk-stratification approaches have limited predictive value, which poses a significant challenge in delivering preventative therapies. Therefore, finding new biomarkers for CVD is of interest and may improve the identification of individuals who would benefit most from preventative therapies. The main aim of this thesis was to identify novel approaches to risk stratification in common CVD states using circulating and imaging biomarkers. This thesis consists of four studies that evaluated: 1) The prognostic role of circulating angiotensin converting enzyme 2 (ACE2) in coronary artery disease (Chapter 3); 2) The role of circulating and myocardial ACE2 in aortic stenosis (Chapter 4); 3) The role of abnormal myocardial tissue characterisation using native T1 time, a cardiac magnetic resonance technique in aortic stenosis (Chapter 5); and 4) The role of opportunistic screening using cardiac computed tomography (CT) to identify markers of vascular disease such as coronary artery calcium and thoracic aortic dilation in atrial fibrillation (Chapter 6). The first study (Chapter 3) was a prospective evaluation of circulating ACE2 levels in patients with obstructive coronary artery disease. ACE2 is an integral membrane protein that degrades angiotensin II and has an emerging role as a circulating biomarker of CVD. Over a median follow up of 10.5 years, circulating ACE2 activity independently predicted the occurrence of major adverse cardiovascular events (MACE) [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.24–4.72]. The second study (Chapter 4) investigated the relationship between circulating ACE2 activity levels and all-cause mortality in patients with aortic stenosis. Additionally, the relationship between circulating ACE2 activity, myocardial ACE2 gene expression, and myocardial fibrosis were examined. Higher circulating ACE2 levels were associated with increased myocardial structural abnormalities such as increased LV mass index and increased LV volumes. Over a median follow-up of 5 years, elevated circulating ACE2 activity was an independent predictor of all-cause mortality with incremental prognostic value after adjustment for relevant clinical, imaging, and biochemical parameters (HR: 2.28; 95% CI: 1.03 to 5.06). In a subset of patients with myocardial tissue collection, increased circulating ACE2 was associated with reduced myocardial ACE2 gene expression and severe myocardial fibrosis. The third study (Chapter 5) investigated whether diffuse myocardial fibrosis characterised by greater native T1 times on cardiac magnetic resonance provides prognostic utility to predict MACE (all-cause mortality or heart failure hospitalisation) in patients severe AS being evaluated for transcatheter aortic valve replacement. Native T1 times were higher than previously reported values in healthy controls. Patients with higher T1 times were more likely to have evidence of myocardial decompensation demonstrated by higher NT-proBNP levels and lower left ventricular ejection fraction. Over a median follow-up of 3.1 years, increased native T1 time (HR:1.68; 95% CI:1.08 - 2.62) and age > 75 years (HR:1.82;1.01–3.28) were independent predictors of MACE. The fourth study (Chapter 6) investigated the prevalence of incidental vascular diseases, including thoracic aortic aneurysmal disease and coronary atherosclerosis, both important causes of cardiovascular mortality, in patients with atrial fibrillation. In a cross-sectional study of 1,000 consecutive patients with atrial fibrillation, one in five were found to have newly identified thoracic aortic aneurysmal disease on multidetector chest CT. A small proportion (1%) had significantly aneurysmal dimensions that approached surgical thresholds. Although two-thirds of the cohort had coronary calcification, 38% were not taking lipid-lowering therapy. The findings therefore represent an opportunity to substantially optimise preventative measures in AF. Overall, the findings of the thesis suggest that the circulating and imaging biomarkers evaluated in the above studies, provide incremental diagnostic and/or prognostic information in patients with CVD. The findings need confirmation in large independent cohorts before these biomarkers can be incorporated into risk stratification algorithms

Left ventricular hypertrophy in experimental chronic kidney disease is associated with reduced expression of cardiac Kruppel-like factor 15

Abstract Background Left ventricular hypertrophy (LVH) increases the risk of death in chronic kidney disease (CKD). The transcription factor Kruppel-like factor 15 (KLF15) is expressed in the heart and regulates cardiac remodelling through inhibition of hypertrophy and fibrosis. It is unknown if KLF15 expression is changed in CKD induced LVH, or whether expression is modulated by blood pressure reduction using angiotensin converting enzyme (ACE) inhibition. Methods CKD was induced in Sprague–Dawley rats by subtotal nephrectomy (STNx), and rats received vehicle (n = 10) or ACE inhibition (ramipril, 1 mg/kg/day, n = 10) for 4 weeks. Control, sham-operated rats (n = 9) received vehicle. Cardiac structure and function and expression of KLF15 were assessed. Results STNx caused impaired kidney function (P < 0.001), hypertension (P < 0.01), LVH (P < 0.001) and fibrosis (P < 0.05). LVH was associated with increased gene expression of hypertrophic markers, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP, P < 0.01) and connective tissue growth factor (CTGF) (P < 0.05). Cardiac KLF15 mRNA and protein expression were reduced (P < 0.05) in STNx and levels of the transcription regulator, GATA binding protein 4 were increased (P < 0.05). Ramipril reduced blood pressure (P < 0.001), LVH (P < 0.001) and fibrosis (P < 0.05), and increased cardiac KLF15 gene (P < 0.05) and protein levels (P < 0.01). This was associated with reduced ANP, BNP and CTGF mRNA (all P < 0.05). Conclusion This is the first evidence that loss of cardiac KLF15 in CKD induced LVH is associated with unchecked trophic and fibrotic signalling, and that ACE inhibition ameliorates loss of cardiac KLF15

Participant characteristics in total cohort and according to plasma ACE2 activity.

<p>Participant characteristics in total cohort and according to plasma ACE2 activity.</p

Clinical events at follow-up.

<p>Kaplan Meier Survival plot illustrating event free survival from major adverse cardiac events (A) and heart failure hospitalisation (B) in patients with coronary artery disease, stratified according to median plasma ACE2 level of 29.3 pmol/ml/min. ACE2 <i>=</i> angiotensin converting enzyme 2.</p

Cox regression analysis for MACE in patients with obstructive CAD.

<p>Cox regression analysis for MACE in patients with obstructive CAD.</p

Long-term prognostic significance of periprocedural myonecrosis in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention

The clinical significance of myonecrosis, measured by cardiac troponin, in the context of percutaneous coronary intervention (PCI) is a matter of ongoing debate. The lack of substantial scientific evidence in this domain is apparent from the ever-changing definitions of periprocedural myocardial infarction and the uncertainty regarding its prognostic relevance.Myonecrosis due to PCI is common and occurs in up to 40% of cases, depending on the definition and biomarker used5. In the Third Universal Definition of Myocardial Infarction (MI), the cutoff cardiac troponin level to diagnose myonecrosis increased from 3 to 5 times the upper reference limit (URL). In contrast to previous definitions, troponin elevation needs to be associated with clinical, electrocardiographic, angiographic or cardiac imagingrelated evidence of ischaemia to be classified as a periprocedural MI, or type 4a MI. However, the occurrence of post-PCI chest pain without troponin elevation and troponin elevation without chest pain, angiographic complications or other signs of ischaemia is well documented. The Society of Cardiovascular Angiography and Interventions (SCAI) has proposed an alternative definition of &ldquo;clinically significant myocardial infarction&rdquo; requiring troponin levels of &ge;70x upper limit of normal (ULN) or &ge;35x ULN with electrocardiographic evidence of infarction